The goal of the proposal is to investigate the potential for Drosophila simulans to be a new and informative model for aging research. Recently, researchers have demonstrated that increased longevity and successful aging in humans is associated with inherited mitochondrial DNA (mtDNA) variants. However, it is not clear whether increased longevity is conferred by: (1) the inherited mitochondrial haplotype, (2) inherited polymorphic variants of nuclear loci, or (3) due to an interaction between inherited nuclear DNA and the specific mitochondrial haplotype. The lack of naturally occurring variation in the mtDNA of current model systems reduces their ability to discriminate alternate mechanisms of increased longevity (1 -3 above). D. simulans is one species that exhibits high mtDNA diversity. This species exhibits three distinct groups of mitochondrial haplotypes (sil, sill, silll) with interhaplotypic divergence approaching 3.0%. Our preliminary data demonstrate acor6lation between specific mtDNA haplotypes and key physiological indicators of aging in E. simulans. MtDNA haplotypes demonstrate differential rates of free radical production, mitochondrial phosphorylative efficiency and differential mean and maximum life spans. We propose to test the expression of the three mtDNA haplotypes in: (1) wild type, (2) introgressed, and (3) randomized nuclear DNA backgrounds with respect to free radical production, mitochondrial phosphorylative efficiency and differential mean and maximum life spans. respect to delineation of the mechanisms by which inherited mtDNA variants give rise to observed variation in rates of aging in humans. Our preliminary data suggest that D. simulans has the potential to be a robust, heuristic model with respect to delineation of the mechanisms by which inherited mtDNA variants given rise to observed variation in rates of aging in humans.